Reactive oxygen (RO) has been identified as an important effector in ageing and lifespan determination. The specific cell types, however, in which oxidative damage acts to limit lifespan of the whole organism have not been explicitly identified. The association between mutations in the gene encoding the oxygen radical metabolizing enzyme CuZn superoxide dismutase (SOD1) and loss of motorneurons in the brain and spinal cord that occurs in the life-shortening paralytic disease, Familial Amyotrophic Lateral Sclerosis (FALS; ref.
Mutations in human CuZn superoxide dismutase (SOD) have been associated with familial amyotrophic lateral sclerosis (FALS). Although leading to many experimental advances, this finding has not yet led to a clear understanding of the biochemical mechanism by which mutations in SOD promote the degeneration of motorneurons that causes this incurable paralytic disease.
Ageing in divergent animal phyla is influenced by several evolutionarily conserved signalling pathways, mitochondrial activity and various environmental factors such as nutrient availability and temperature. Although ageing is a multifactorial process with many mechanisms contributing to the decline, the intracellular accumulation of damaged proteins and mitochondria is a feature common to all aged cells.
Uncoupling proteins (UCPs) can dissipate mitochondrial protonmotive force by increasing the proton conductance of the inner membrane and through this effect could decrease ROS production, ameliorate oxidative stress and extend lifespan. We investigated whether ubiquitous, pan-neuronal or neurosecretory cell-specific expression of human UCP3 (hUCP3) in adult Drosophila melanogaster affected lifespan.
Although autophagy has widely been conceived as a self-destructive mechanism that causes cell death, accumulating evidence suggests that autophagy usually mediates cytoprotection, thereby avoiding the apoptotic or necrotic demise of stressed cells. Recent evidence produced by our groups demonstrates that autophagy is also involved in pharmacological manipulations that increase longevity. Exogenous supply of the polyamine spermidine can prolong the lifespan of (while inducing autophagy in) yeast, nematodes and flies.
There is a substantial distinction to be made between the genetics of aging and the genetics of exceptional longevity. Twin studies suggest that the average set of genetic variations facilitates the average human's ability to live well into their octogenarian years. Other studies indicate that taking full advantage of this average set results in spending the majority of those years in good health. However, many people counteract such genetic endowment with poor health habits, resulting in a substantially lower average life expectancy and relatively more time spent in poor health.
An increasing number of genes required for mitochondrial biogenesis, dynamics, or function have been found to be mutated in metabolic disorders and neurological diseases such as Leigh Syndrome. In a forward genetic screen to identify genes required for neuronal function and survival in Drosophila photoreceptor neurons, we have identified mutations in the mitochondrial methionyl-tRNA synthetase, Aats-met, the homologue of human MARS2. The fly mutants exhibit age-dependent degeneration of photoreceptors, shortened lifespan, and reduced cell proliferation in epithelial tissues.
An increasing body of evidence indicates a role for oligomers of the amyloid-? peptide (A?) in the neurotoxicity of this peptide and the pathology of Alzheimer's disease (AD). Several neurotoxic oligomeric forms of A? have been noted ranging from the larger Amyloid ?-Derived Diffusible Ligands (ADDLs) to smaller trimers and dimers of A?. More recently a dodecameric form of A? with a 56 kDa molecular weight, denoted A?*56, was shown to cause memory impairment in AD model mice.
Mutations in the fused in sarcoma/translated in liposarcoma gene (FUS/TLS, FUS) have been identified in sporadic and familial forms of amyotrophic lateral sclerosis (ALS). FUS is an RNA-binding protein that is normally localized in the nucleus, but is mislocalized to the cytoplasm in ALS, and comprises cytoplasmic inclusions in ALS-affected areas. However, it is still unknown whether the neurodegeneration that occurs in ALS is caused by the loss of FUS nuclear function, or by the gain of toxic function due to cytoplasmic FUS aggregation.
A number of neurological diseases are caused by mutations of RNA metabolism-related genes. A complicating issue is that whether under- or overfunction of such genes is responsible for the phenotype. Polyglutamine tract binding protein-1, a causative gene for X-linked mental retardation, is also involved in RNA metabolism, and both mutation and duplication of the gene were reported in human patients. In this study, we first report a novel phenotype of dPQBP1 (drosophila homolog of Polyglutamine tract binding protein-1)-mutant flies, lifespan shortening.